Theoretical insights into unraveling the mechanism, selectivity patterns, and ligand effects in gold(i)-catalyzed annulations between ynamides and isoxazoles

Abstract

This cutting-edge research work presents a comprehensive and in-depth theoretical investigation into the mechanism of Au(I)-catalyzed annulations between ynamides and 1,2-benzisoxazoles, as well as the chemoselectivity of the reactions in the presence of different ligands (L = JohnPhos, IPr) and the factors influencing the Z/E-configuration of the resulting 6-membered cyclic products. State-of-the-art density functional theory calculations reveal that (i) the reaction mechanism involves three distinct processes: process 1 corresponds to the transformation of a gold-π-alkyne precursor into a gold–carbene intermediate; process 2 involves the conversion of gold–carbene intermediates into 6-membered/7-membered cyclic intermediates; process 3 involves the conversion of 6-membered/7-membered cyclic intermediates to furnish 6-membered/7-membered cyclic products, respectively. (ii) The distinct chemoselectivity exhibited by the two ligands, JohnPhos and IPr, has been thoroughly explored through distortion/interaction analysis. The distortion energy is responsible for ligand-controlled chemoselectivity. (iii) The Z/E-configuration of 6-membered cyclic products is determined by the N-attack step of 1,2-benzisoxazole on the gold-π-alkyne. These theoretical findings hold significant implications for synthetic chemists, providing valuable insights into the design of novel catalytic systems and the prediction of reaction pathways and selectivity patterns in related organic transformations involving ynamides and isoxazoles.